Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, how HBV may induce HCC remains controverisal. By producing transgenic mice carrying the entire HBV genome, we have recently discovered that HBV can significantly increase the risk for HCC if the mice are exposed to a low dose of diethylnitrosamine (DEN), a widespread carcinogen. The goal of this research application is to continue to use this model system to understand the molecular mechanisms that regulate HBV replication and oncogenesis. There are three specific aims. Aim 1 is to study the role of androgen and its receptor on HBV replication and oncogenesis. Our preliminary studies indicate that the HBV X protein (HBx) can bind to androgen receptor (AR) and enhance its gene transactivation activity. This observation raises the possibility that AR may regulate HBV replication and oncogenesis via its interaction with HBx. The goal of this aim is to investigate this possibility. Aim 2 is to study the mechanism of HBV-induced hepatocellular carcinogenesis. Our preliminary studies indicate that HBV can significantly increase the risk for HCC if the mice are exposed once to DEN. The goal of this aim is to use this model system to further investigate how HBV interacts with DEN to induce hepatocarcinogenesis. Aim 3 is to study the role of a natural HBV mutant in HBV replication and oncogenesis. This mutant carries a double-nucleotide mutation in the core promoter and is associated with chronic hepatitis and an increased risk for HCC. The goal of this aim is to investigate whether liver injury favors the selection of this mutant and whether and how this mutant is more oncogenic than the wild-type virus. Relevance to Public Health Hepatitis B virus (HBV) can cause severe liver diseases including liver cancer. The goal of this application is to use a mouse model that produces HBVto understand howthis virus replicates and causes liver cancer. This research will lead to a better understanding of the HBV life cycle and facilitate the development of therapeutic options for HBV patients.